PREVALENT: The Role of Pioglitazone in Vascular Transcriptional Remodeling
Study Details
Study Description
Brief Summary
Acute myocardial infarction (AMI) remains the leading cause of death worldwide. In this scenario, early coronary reperfusion is the main therapeutic strategy as it substantially reduces mortality. Paradoxically, however, reperfusion triggers additional tissue damage that accounts for about 50% of the infarcted heart mass, i.e., ischemia and reperfusion injury (IRL). In this context, sphingosine-1-phosphate (S1P) is a sphingolipid synthesized by sphingosine kinases (Sphk), carried in plasma bound to high-density lipoprotein (HDL) and released after cellular damage such as LIR. Particularly, in animal models of AMI, therapies targeting downstream S1P receptor signaling triggered by HDL/S1P are able to promote endothelial barrier functions and attenuate secondary damage to LIR. Thus, the molecular control of sphingosine kinase 1 (Sphk1) transcription during LIR in vivo or during hypoxia/reoxygenation (H/R) in vitro may represent an important mechanism for maintaining endothelial homeostasis since it promotes the generation of S1P and this may promote subsequent HDL enrichment. Thus, the role of pioglitazone hydrochloride 45mg/day or placebo for five days in volunteers undergoing coronary artery bypass grafting (BVR) will be investigated in order to verify the vascular expression of SPhk1, transcriptome and vascular proteome remodeling, as well as S1P content in HDL.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 4 |
Detailed Description
This will be a prospective, randomized, double-blind clinical study. Participants will be randomized into two blocks, whose order will be maintained by an independent researcher, and will not be opened until the end of data analysis. From a sample of patients admitted to be admitted to coronary artery bypass graft surgery, followed in the cardiac surgery outpatient clinic, 20 research participants, male, non-diabetic, over 40 years of age, mass index Body weight (BMI) between 20 and 34.9kg/m2, who will be followed up at Hospital de Clínicas/UNICAMP and randomized to receive placebo or pioglitazone hydrochloride 45mg/day for 5 days before surgery. The amount of S1P in HDL in a baseline condition (before surgery) will be evaluated in groups. This same measurement will be repeated on day 5 (coincident with the day of surgery) after using pioglitazone hydrochloride 45mg/day or placebo. In addition, on the day of surgery, a saphenous vein fragment measuring approximately 2 cm and an internal thoracic artery fragment measuring approximately 1 cm will be collected, which will not impair the quality of the graft or the extent of the material to be used as a graft, since vascular material is abundant in this case. In addition, the results of serum troponin levels in the first 24h post-SVR (6, 12, 24h) will be evaluated to estimate the extent of troponin release between groups. Postoperative examination.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Pioglitazone Research participants will be randomized to receive pioglitazone hydrochloride 45mg/day for 5 days prior to coronary artery bypass surgery. |
Drug: Pioglitazone 45 mg
We investigated the role of pioglitazone hydrochloride 45mg/day for five days in patients admitted for coronary artery bypass grafting (CABG) in order to investigate vascular SPhk1 expression, vascular transcriptome and proteome remodeling, as well as S1P content in HDL
Other Names:
|
| Placebo Comparator: Placebo Research participants will be randomized to receive placebo for 5 days prior to coronary artery bypass surgery. |
Drug: Placebo
We investigated the role of placebo for five days in patients admitted for coronary artery bypass grafting (CABG) in order to investigate vascular SPhk1 expression, vascular transcriptome and proteome remodeling, as well as S1P content in HDL
|
Outcome Measures
Primary Outcome Measures
- HDL-S1P change [Five days]
Change in S1P content of isolated HDL between baseline and after treatment with pioglitazone hydrochloride 45 mg/day
Secondary Outcome Measures
- SPHK1 - internal thoracic artery [Five days]
Difference in SPHK1 expression in the internal thoracic artery cells determined by western blot between groups
- S1PR1 - saphenous vein [Five days]
Difference in S1P receptor (S1PR1) expression in saphenous vein endothelial cells determined by western blot between groups
- SPHK1 - aortic artery [Five days]
Difference in SPHK1 expression in the aortic artery cells determined by western blot between groups;
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Male individuals
-
Individuals undergoing CABG surgery for coronary artery disease
-
Be over 40 years of age
-
BMI between 20 and 34.9kg/m2
Exclusion Criteria:
-
Diabetes, BMI greater than 35 kg/m2, steatohepatitis, chronic kidney disease, systemic vasculitis, conditions that induce systemic inflammation such as psoriasis and systemic lupus erythematosus
-
contraindications to the use of pioglitazone hydrochloride (heart failure, liver failure - AST or ALT > 2.5x upper normal limit, history of bladder cancer or macroscopic hematuria without investigation)
-
moderate or severe valve disease
-
need for concomitant use of other hypoglycemic therapies during hospitalization, particularly insulin
-
peripheral edema
-
recent hospitalization
-
known allergy to any study drug
-
polyuria, polydipsia, weight loss, or other clinical signs of volume depletion or diabetes, difficult-to-control systemic arterial hypertension, defined as individuals taking 4 or more drugs
-
those who withdraw the Informed Consent Form (TCLE), or who, for some reason, are not able to sign or understand the TCLE
-
history of gastrointestinal disorders that may interfere with study drug absorption
-
research participant who is participating in other clinical trials or whose participation ended less than six months ago
-
Research participant who has left ventricular dysfunction
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Campinas | Campinas | SP | Brazil | 13083-887 |
Sponsors and Collaborators
- University of Campinas, Brazil
Investigators
- Principal Investigator: Andrei Sposito, Professor, University of Campinas, Brazil
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- PREVALENT